In silico (computed) modelling of doses and dosing regimens associated with morphine levels above international legal driving limits
View/ Open
Date
2018-05-04Author
Boland, Jason W
Johnson, Miriam J
Ferreira, Diana
Berry, David J
Metadata
Show full item recordAbstract
Background: Morphine can cause central nervous system side effects which impair driving skills. The legal blood morphine
concentration limit for driving is 20 μg/L in France/Poland/Netherlands and 80 μg/L in England/Wales. There is no guidance as to the
morphine dose leading to this concentration.
Aim: The in silico (computed) relationship of oral morphine dose and plasma concentration was modelled to provide dose estimates
for a morphine plasma concentration above 20 and 80 μg/L in different patient groups.
Design: A dose–concentration model for different genders, ages and oral morphine formulations, validated against clinical
pharmacokinetic data, was generated using Simcyp®, a population-based pharmacokinetic simulator.
Setting/participants: Healthy Northern European population parameters were used with age, gender and renal function being
varied in the different simulation groups. In total, 36,000 simulated human subjects (100 per modelled group of different ages and
gender) received repeated simulated morphine dosing with modified-release or immediate-release formulations.
Results: Older age, women, modified-release formulation and worse renal function were associated with higher plasma concentrations.
Across all groups, morphine doses below 20 mg/day were unlikely to result in a morphine plasma concentration above 20 μg/L; this
was 80 mg/day with the 80 μg/L limit.
Conclusion: This novel study provides predictions of the in silico (computed) dose–concentration relationship for international
application. Individualised morphine prescribing decisions by clinicians must be informed by clinical judgement considering the individual
patient’s level of impairment and insight irrespective of the blood morphine concentration as people who have impaired driving will be
breaking the law. Taking into account expected morphine concentrations enables improved individualised decision making.
Description
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.